A proteasome is a multi subunit proteolytic complex that degrades ubiquitinylated proteins into small peptides. The molecular and functional characteristics of the ubiquitin-proteasome system (UPS) has been studied by several groups showing that 26S proteasome is involved in a diverse array of biological processes including cell cycle progression, apoptosis, DNA repair, immune response, signal transduction, transcription, metabolism, protein quality control and developmental programs. Proteins that control such processes are subjected to proteolysis in a precise, rapid and timely manner by the 26S proteasome. Thus UPS has been reported to play a crucial role in tumorigenesis, inflammation and autoimmunity. The anticancer activity of the proteasome inhibitors has shown selective apoptosis in malignant cells, and represented a new class of antineoplastic agents. Subsequently proteasome has emerged as a promising target in search of cancer therapeutics in the recent years. Bortezomib (Velcade), Salinosporamide A, Carfilzomib represent three classes of proteasome inhibitors that have been clinically approved or in clinical trial for treatment of multiple myeloma and/or mantle cell lymphoma. However, drug resistance caused by several mechanism has emerged as a major challenge for protreasome associated cancer therapy. Studies with combination of the two agents (Bortezomib and Salinosporamide A) have suggested that combination of agents that have qualitatively different mechanism of action may become the solution to the drug resistance. Therefore developing novel molecules as proteasome inhibitors is essential for cancer therapy.